The use of medicaments that are administered using inhalers is targeted particularly on interactions with particular regions of the respiratory system of a patient. These regions comprise the nasal passages, the pharynx and various places within the lungs, such as the bronchi, bronchioles and alveoli. The possibility of administering medicaments to one of these target regions is dependent inter alia on the aerodynamic diameters of the respective particles or droplets which are breathed in when the inhaler is used. The current assumption is that particles with aerodynamic diameters of between 2 and about 5 microns can be supplied satisfactorily to the bronchi and bronchioles. Smaller particles may potentially penetrate into the alveoli. Particles with an aerodynamic diameter of more than 6 microns and especially more than 10 microns are typically suitable for deposition in the pharynx and nasal passages.
In the case of inhalers which are intended to deliver a medicament into the lung, it is generally desirable if a large proportion of the medicament administered, particularly with respect to the particle size, is inhalable and it is possible to achieve a high deposition rate of the medicament in the lung itself. This depends on a number of factors such as, in particular, the properties of a spray mist produced with the inhaler. These properties are, for example, the speed of the mist, the size of the particles and their size distribution, the proportion of small particles, the constituents of the gas, etc.
The following description will concentrate on the administration of powdered formulations, but is also applicable to the administration of liquid formulations.
Many powder inhalers are already on sale or are otherwise known. A distinction is made between two types of inhalers: active and passive. In passive inhalers, the inward breath of the user or patient alone is used to break up the powder and carry the powder into the lungs. The carrying and breaking up of the powder are therefore dependent on the flow rate at which the patient breathes air in through the apparatus. As a result, the inhalable content or the part of the powder that actually reaches the lungs is highly dependent on the breathing behaviour of the patient and varies from one patient to the next. Active inhalers, unlike passive inhalers, contain an additional energy source which assists with the break-up and conveying of the powder. The powder is actively nebulised with apparatus of this kind.
Active inhalers, with their high market share over many years, are in particular conventional propellant-driven metering aerosols (hereinafter frequently referred to by the conventional English abbreviation MDI, standing for “metered dose inhaler”). In an MDI the medicament is present as a suspension or solution in a propellant. The propellant is contained under excess pressure in a container with a metering valve. On activation, the metering valve delivers a single measured amount (dose) of the medicament in the form of a gas stream. Propellants suitable for MDIs may contain hydrofluoroalkanes (HFA) or other fluorohydrocarbons (FHC) with low boiling points. Because of the high pressure difference between the inside of the propellant container (typically around 5 bar) and the ambient air (1 bar), in conventional MDIs the propellant is expelled at a high speed which may even enter the supersonic speed range. As a result, the time for emptying the valve chamber and hence the duration of a nebulisation is so short (typically about 50 milliseconds when delivering 100 microliters) that it is difficult for a patient to adapt their breathing to the short pulse such that they are actually able to breathe in the entire volume nebulised. Moreover, the propellant is partially expelled from the apparatus in liquid form. As a result, and because of the high exit speed, a large proportion of the medicament is delivered in such a coarse form that it is deposited directly in the patients' oropharyngeal cavity without being able to be carried into the lungs.
WO2004110536A1 shows a delivery device for a powdered medicament in which a receptacle containing powdered medicament and a propellant source are arranged in a housing such that the propellant strikes the powdered medicament through an inlet. In the receptacle, the aerosol thus formed is able to expand before being expelled from the device through an exit opening. For the device, replacement inserts are provided with combined powder and propellant inserts. Possible propellant sources specified are compressed gases such as carbon dioxide, nitrogen or air, or fluorohydrocarbons such as HFA-134a or HFC-227 are mentioned as conventional propellants. Within the scope of tests for clinical trials, the specification WO2004110536A1 mentions, inter alia, nebulisation results for device configurations having receptacles filled with 120 milligrams of micronized active substance and nitrogen as propellant at pressures of 6 to 14 bar. In comparison to the test data described, standard commercial (not capsule-based, usually passive) powder inhalers as a rule deliver powder units of the order of 6 to 400 micrograms in size per application (when capsules are used, larger amounts of filling are known; thus, a capsule-based powder inhaler is also known in which the capsule holds 28 milligrams). The widely used MDIs based on delivery using propellants typically deliver only about 200 micrograms of active substance per application. Inhalers for delivering larger amounts of formulation are not available on the market in this context, as far as the inventors are aware.
The specification U.S. Pat. No. 4,534,345 shows, for example, an active inhaler which contains a propellant container, a storage chamber with pharmaceutically active substance in solid, micronized form and a dose charging device with a perforated membrane. In a first position, perforations in the membrane are filled with the substance, in a second the perforations are pushed into a channel for the propellant. When an associated device is actuated, the propellant is released from its container into the channel and expels the substance through a nozzle of the inhaler.
Inhalers for dry powder are divided into devices for administering individual dosage units and into multi-dose devices. Multi-dose devices are also subdivided into devices with pre-metered and individually stored dosage units (the usual abbreviation “pmDPI” is used, from the corresponding English term “pre-metered Dry Powder Inhaler” and devices in which each powder unit is measured out from a reservoir inside the device by means of a measuring device.
The use of pmDPIs has the advantage that the individual dosage units are measured out under controlled factory conditions and the powder can be protected comparatively easily from the ambient air and other external influences. In many applications a formulation is used in the form of a mixture of an active substance and a carrier substance such as lactose. The lactose and/or the active substance or active substances tend to absorb moisture from the ambient air, thus resulting in clumping of the powder and difficulties in breaking it up or nebulising it and in delivering the powder into the lungs.
The specification DE4106379A1 shows a passive inhaler in which the powder is contained in pre-metered inhalable amounts in pouches of a flexible strip-like carrier. This carrier consists of a carrier web forming the pouches and a cover strip that closes off the pouches. The inhaler comprises, in addition to a receptacle for the powder carrier, an opening station with a pulling device which pulls the cover strip and the carrier web apart in order to open the pouches. Powder can be aspirated from the opened pouch through a powder outlet.
The specification EP1992381A1 discloses an active pmDPI with an annular storage device that can be rotated step by step, with a plurality of inserts, each insert containing a single dose of a medicinal formulation in a storage chamber and a nozzle. The inserts are contained in separate, sealed cavities which are opened individually to deliver the individual dose. To expel the dose, the respective insert is connect by means of a connecting element to an air pump with bellows.
A similar active pmDPI is disclosed in the specification WO2009040044. This additionally shows that the connecting element between the pump and the insert constitutes a construction which, together with the air pump, forms a resonance system. This resonance system operates such that the build-up of pressure of the compressed air produced by the air pump does not rise in a strictly uniform manner during the delivery of the dose but is modulated in pulsed manner.
The specification WO2009083244A2 shows an active pmDPI in which the individual doses of the medicinal formulation are contained in storage units in an oblong carrier. Apart from a storage chamber with formulation each storage unit comprises a nozzle for individually releasing the respective dose. In one embodiment, the nozzles are exposed one after another by the removal of a cover strip. To expel the formulation from the individual storage units the associated storage chamber is also pierced with a piercing element, allowing pressurised gas to enter the storage chamber, thereby carrying the formulation with it. The pressurised gas is provided by an air pump or alternatively from a container holding liquefied gas. In one embodiment, the delivery of the respective dose by compressed air is triggered by detection of an inward breath.
The specification GB2233236A shows an MDI with so-called breath actuation. In this device, a measured dose is conveyed from a pressurised container, with medicament suspended or dissolved in liquid propellant, into a storage chamber in which a valve in a closed position closes off the outlet. The valve, e.g. a magnetic plate valve or a piston valve provided with a restoring spring, is part of a delivery device controlled by the patient's inhalation.
The problem which the present invention addresses is to provide a device which is an improvement on the prior art, for nebulising preferably powdered medicinal formulations for inhalation. In particular a device is to be provided in which comparatively large measured amounts of substance, particularly greater than 1 milligram of active substance, can be expelled for inhalation or with which large inhalable dosage amounts of the medicinal formulation can be prepared. Particularly preferably, in the embodiment of the device as an inhaler, the pulmonary fraction of a quantity of formulation delivered in aerosol form with this device should be only slightly, or not at all, dependent on the breathing characteristics of the user, i.e. the patient. Moreover, the device should be configured advantageously, particularly in terms of the aspect of error-free use by a user, particularly with regard to the coordination of the breathing characteristics with the nebulisation.